Abnormalities of phase, amplitude and waveform of circadian rhythms have been reported in depression and in manic-depressive illness. Abnormalities of the circadian system are thought to play an important role in the illnesses because experimental manipulations of sleep and circadian rhythms are capable of altering clinical state. The human circadian system has been mathematically modeled by a two process or two oscillator system. Depressive sleep abnormalities and the therapeutic effect of various sleep manipulations have also been modeled by changing certain parameters in these mathematical models, such as the intrinsic period of a circadian oscillator or the rates of accumulation and discharge of a sleep factor. We are testing these and other predictions of the models by studying circadian rhythms in patients while they live in isolation from all external time cues in special rooms on the 4-West research unit. Patients stay in the rooms while rectal temperature, wrist motor activity, sleep EEG and behavioral events are continuously monitored by computer. In these conditions circadian rhythms "free-run" according to their own intrinsic period, which is normally about 25 hours. To date four affective patients have been studied for one month each. In one bipolar patient who switched from depression to mania shortly after beginning the experiment, the free-running period was abnormally short (less than 24 hours). Such an abnormally fast circadian pacemaker could explain phase-advanced circadian rhythms under conditions of entrainment to external time cues. A manic patient showed internal dysynchronization of sleep and temperature circadian rhythms with a sleep-wake cycle period of 17 hours. The circadian period in two other cases was normal. All cases showed markedly abnormal ratios of sleep to wakefulness during the experiments, indicating that changes in timing and amount of sleep in depression are fundamentally endogenous and do not depend on some interaction with the environment.